Nicotinic Receptor Regulation of Dopamine Transporter

多巴胺转运蛋白的烟碱受体调节

• 批准号: 6989377
• 负责人: Linda P Dwoskin
• 金额: $ 21.63万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6989377
• 关键词: amygdala; biological models; corpus striatum; dopamine transporter; dosage; drug receptors; laboratory rat; neuropharmacology; neurotransmitter transport; nicotine; nicotinic receptors; nucleus accumbens; prefrontal lobe /cortex; protein structure function; psychopharmacology; receptor expression; reinforcer; smoking; tobacco abuse

DESCRIPTION (provided by applicant): Tobacco use is the number one preventable cause of death in the US. The reinforcing efficacy of nicotine (NIC), the most abundant alkaloid in tobacco, plays a major role in the maintenance of tobacco smoking. Furthermore, tobacco use and depressive disorders are highly comorbid, and NIC maybe be used in part to alleviate depression in this clinical population. Research on the neurobiology of reward and drug addiction has focused on mesocorticolimbic and nigrostriatal dopamine (DA) pathways. NIC activates nicotinic receptors which increases extracellular DA concentrations at both terminal and cell body regions of these pathways. Extracellular DA concentration is the net result of neurotransmitter release from the presynaptic terminal and neurotransmitter clearance from the extracellular space. DA clearance is mediated primarily by the plasma membrane dopamine transporter (DAT). Although there is a wealth of information on NIC stimulated DA release, the ability of NIC to modulate DAT function and the underlying mechanisms responsible for this effect have not been studied in detail. Preliminary data show that in prefrontal cortex, acute NIC increases DA uptake into synaptosomes, DA clearance in in vivo voltammetry studies and DAT trafficking to the cell surface. Thus, NIC augmentation of DAT function appears to sharpen the kinetics of the NIC-induced increase in extracelluar DA concentration in prefrontal cortex. The proposed study will begin to elucidate the underlying mechansims responsible for the NIC-induced enhancement of DAT function. The hypothesis to be tested in the current application is that NIC, via nicotinic receptor activation, mediates the trafficking of DAT. This hypothesis will be tested using the rat as the animal model, and will determine (1) the dose-related effects of acute in vivo administration of NIC on DAT trafficking in striatum, nucleus accumbens, prefrontal cortex and amygdala; (2) if nicotinic receptors mediate the effect of NIC on DAT trafficking; and (3) the effect of intermittent and continuous NIC administration on DAT trafficking. Results of these experiments will begin to elucidate the cellular mechanisms by which NIC and nicotinic receptors modulate DAT function, and thereby, contribute to the regulation of extracellular DA concentration. Thus, insight will be provided with respect to the effect of NIC on DA neurotransmission in brain regions associated with drug abuse.

描述（由申请人提供）：烟草使用是美国头号可预防的死亡原因。尼古丁（NIC）是烟草中含量最丰富的生物碱，其增强作用在维持吸烟中起着重要作用。此外，烟草使用和抑郁症是高度共病的，NIC可能部分用于缓解该临床人群的抑郁症。奖赏和药物成瘾的神经生物学研究主要集中在中脑皮质边缘和黑质纹状体多巴胺（DA）通路。NIC激活烟碱受体，增加这些途径的末端和细胞体区域的细胞外DA浓度。细胞外DA浓度是突触前末梢释放神经递质和细胞外间隙清除神经递质的净结果。DA清除主要由质膜多巴胺转运蛋白（DAT）介导。虽然有丰富的信息NIC刺激DA释放，NIC调节DAT功能的能力和负责这种效果的潜在机制还没有详细研究。初步数据表明，在前额皮质，急性NIC增加DA摄取到突触体，DA清除在体内伏安法研究和DAT贩运到细胞表面。因此，NIC增强DAT功能似乎使NIC诱导的前额叶皮层细胞外DA浓度增加的动力学更加尖锐。拟议的研究将开始阐明负责NIC诱导的DAT功能增强的潜在机制。在本申请中待检验的假设是NIC通过烟碱受体活化介导DAT的运输。将使用大鼠作为动物模型检验该假设，并将确定（1）NIC的急性体内给药对纹状体、丘脑核、前额皮质和杏仁核中DAT运输的剂量相关效应;（2）烟碱受体是否介导NIC对DAT运输的影响;（3）间歇和连续给予NIC对DAT运输的影响。这些实验的结果将开始阐明NIC和烟碱受体调节DAT功能的细胞机制，从而有助于调节细胞外DA浓度。因此，将提供关于NIC对与药物滥用相关的大脑区域中的DA神经传递的影响的见解。